Two aspects of the regulation of myocardial energy generation are being investigated in this research program. A detailed study is being conducted concerning the mechanism(s) regulating the pyruvate and ketoglutarate dehydrogenase multienzyme complexes of cardiac and other tissues. These control mechanisms are being delineated at the level of the isolated enzyme complex, the mitochondrion and intact tissue. The effects of various nucleotides, coenzyme A derivatives and other metabolites are being investigated. A related study is being conducted on the effects of guanine nucleotides on the coupling mechanism between catecholamine receptors and the adenylate cyclase and the relationship of these nucleotide effects in intact tissues to the effects of guanine nucleotides on other cellular control mechanisms. The second aspect of this research involves the elucidation of divalent metal cation-mediated control mechanisms in cardiac tissue. The presence of divalent metal cation binding sites on subcellular membranes being studied in cardiac tissue. The energy dependence, the effects of a variety of effector molecules and the specificity of binding and release are being considered. The major premise being tested is that divalent cations may be retained by various cellular membranes to be released under one set of metabolic or energetic conditions and re-accumulated by the membrane under an alternate set of conditions. Further it is proposed to evaluate the effect of this on-off movement on the regulation of various cellular processes including neurotransmitter release, adenylate cyclase activity, mitochondrial energy generation etc. The significance of this research derives from the importance to elucidate the integrated regulatory mechanisms involved in the life sustaining, energy generating function of various tissue.